This NIH mentored Career Development Award proposal describes a three-year training program for the candidate, a physician-scientist with the long-term goal of becoming an independent academic investigator. The candidate aims to become an expert in mucosal immunology and microbiology with a research focus on understanding the factors controlling the acquisition of the intestinal microbiota and subsequent effects on programming of the intestinal immune response. To accomplish these goals, the candidate and her mentors put forward an integrated plan encompassing novel scientific ideas, advanced training in immunology and microbiology and a detailed career development plan. The candidate proposes to build on preliminary work on the early microbiota to mechanistically understand the role of maternal high fat diet (HFD) on altering offspring gut bacterial composition, the Th17 response and susceptibility to intestinal injury. Preliminary work by the candidate has shown that there is active immune regulation of the transition of the microbiota from birth into adulthood in conventionally raised mice. Additionally, 1-week-old mouse pups born to mothers on a 60% HFD were found to have a unique microbiota, different from age-matched controls born to mothers on regular chow. HFD offspring were also found to have increased expression of the pro-inflammatory cytokine IL-17 in the colon, which is primarily produced by Th17 cells, and increased susceptibility to early (10-day-old) and late (adult) models of intestinal injury. The central hypothesis for this proposal is that epigenetic alteration in HFD offspring results in a unique microbiota, and combined with factors in breast milk, directly affects the development of the Th17 axis, predisposing to intestinal injury. 3 specific aims will be examined: 1) To examine how the microbiota alters the intestinal Th17 response in HFD offspring, 2) To determine how epigenetics or breast milk (BM) alter the microbiota and Th17 response in HFD offspring and 3) To examine whether probiotics can modulate the susceptibility to intestinal injury in HFD offspring. An innovation in this proposal is the focus o fetal origins of intestinal inflammatory diseases caused by maternal HFD. This study will provide insight into how maternal diet alters the offspring microbiota and consequent immune intestinal regulation to contribute to the programming of inflammatory disease. It has particular relevance in Necrotizing Enterocolitis and Inflammatory Bowel Disease and may contribute to the development of novel treatment strategies.